Chronic kidney disease is present in a large proportion of adults with sickle cell disease (SCD) and is associated with increased morbidity and early mortality. The mechanisms for how chronic kidney disease develops are, unfortunately, poorly understood and therapies to prevent and treat sickle cell nephropathy are urgently needed. This proposal will leverage robust preliminary data from the applicant's K23 and R03 awards to innovatively address the mechanistic pathways and susceptibilities for kidney disease and investigate targeted interventions to mitigate kidney damage in SCD. The underlying hypothesis is that cell-free hemoglobin mediates damage to the kidney cortex and microvasculature if not efficiently scavenged and processed. The applicant will apply exciting preliminary data to test this hypothesis via three specific aims. Specific aim #1 will determine whether functional variants in HP, the main scavenger of cell-free hemoglobin in circulation, and HMOX1, the rate limiting enzyme for degrading heme, are associated with acute kidney injury risk during a vaso-occlusive crisis, when concentrations of cell-free hemoglobin increase approximately 2-fold. Specific aim #2 will determine whether cell-free hemoglobin leads to kidney microvascular dysfunction through aberrant function of thrombomodulin, an endothelial bound protein critical for maintaining vascular health. Specific aim #3 will investigate whether voxelotor, an oral small molecular inhibitor of sickle hemoglobin polymerization and hemolysis, reduces cell-free hemoglobin exposure and damage to the kidney in transgenic sickle mice. Integrating genetic analyses of cell-free hemoglobin processing with therapies to improve vascular function or reduce cell-free hemoglobin exposure to the kidney will lead to a deeper understanding for the mechanisms of kidney damage and guide individualized and preventive therapeutic strategies for sickle cell nephropathy. This research team is exceptionally positioned to achieve the goals outlined in this proposal through a strong history of productivity and the institutional environment. The University of Illinois at Chicago Comprehensive Sickle Cell Center cares for over 800 SCD patients and has a long-standing tradition of successful implementation of research studies. At the present time, there are only limited therapeutic options available to treat SCD. Developing a better understanding of the susceptibilities and pathways for kidney disease may potentially have a significant impact on this underserved high risk population.